US4910214A - Optical isomer of an imidazole derivative medetomidine as an alpha-2-receptor agonist - Google Patents

Optical isomer of an imidazole derivative medetomidine as an alpha-2-receptor agonist Download PDF

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US4910214A
US4910214A US07/219,637 US21963788A US4910214A US 4910214 A US4910214 A US 4910214A US 21963788 A US21963788 A US 21963788A US 4910214 A US4910214 A US 4910214A
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medetomidine
enantiomer
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Arto J. Karjalainen
Raimo E. Virtanen
Eino J. Savolainen
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to optical isomers of imidazole derivatives and to their preparation.
  • the acid addition salts can be converted back to the free bases by making their aqueous solutions alkaline with sodium hydroxide and by extracting the liberated base in an appropriate organic solvent such as methylene chloride.
  • the d- and l-enantiomers of medetomidine react with organic and inorganic acids to form the corresponding acid addition salts, which have the same therapeutic activities as the bases. They can thus form many pharmaceutically usable acid addition salts, as, for instance, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
  • the d- and l-enantiomers of medetomidine are selective and potent ⁇ 2 -receptor agonists.
  • Adrenergic receptors are physiologically important binding sites which are specific to noradrenaline and adrenaline and located on the surface of the cell membrane.
  • the adrenoceptors of the sympathetic nervous system have been classified into two different subtypes, alpha-( ⁇ ) and beta-( ⁇ ) receptors, which can be further divided into two subgroups, viz ⁇ 1 and ⁇ 2 and ⁇ 1 and ⁇ 2 .
  • alpha-( ⁇ ) and beta-( ⁇ ) receptors which can be further divided into two subgroups, viz ⁇ 1 and ⁇ 2 and ⁇ 1 and ⁇ 2 .
  • ⁇ 1 , ⁇ 2 and ⁇ 1 are mainly located post-synaptically on the surface of, e.g., smooth muscle and thus mediate, e.g., smooth muscle contraction or relaxation; whereas ⁇ 2 receptors are mainly located presynaptically on the terminals of noradrenergic nerves.
  • ⁇ 2 -receptors are stimulated by noradrenaline under physiological conditions noradrenaline release is blocked, i.e. there is a negative feed-back phenomenon.
  • This negative feed-back phenomenon may also be induced by certain synthetic ⁇ 2 -agonists like medetomidine and some of its near derivatives.
  • the d- and l- enantiomers of the present invention and especially the d-enantiomer have proved to possess highly enhanced ⁇ 2 -selectivity and potency compared to the racemic mixture (i.e. medetomidine).
  • the d-enantiomer can be expected to be of value, e.g., as a sedative-analgesic, anxiolytic or antihypertensive agent. Furthermore, it can be used as a pharmacological tool in the study of the physiology and pharmacology of ⁇ 2 -adrenoceptors.
  • ⁇ 2 -agonism was determined by means of isolated, electrically stimulated mouse was deferens preparation (Marshall et al., Br. J. Pharmac. 62, 147-151, 1978). In this model, an ⁇ 2 -agonist is able to block electrically induced muscular contractions by activating the presynaptic ⁇ 2 -adrenoceptors and thus diminishing the secretion on the motor transmitter.
  • Known ⁇ 2 -agonists like detomidine, medetomidine and clonidine were used as reference substances. Results are shown in Table 1, where the ⁇ 2 -agonist effect is presented as the pD 2 -value (negative logarith of the molar concentration of the compound producing 50 percent of maximal inhibition.)
  • the selectivity of the d-enantiomer as an ⁇ 2 -agonist was studied in receptor binding experiments using rat brain membranes.
  • the ability of the d-isomer and the reference compounds to compete with 3 H-clonidine (for ⁇ 2 -receptors) and 3 H-prazosin (for ⁇ 1 -receptors) was studied essentially as described by Virtanen and Nyman in Eur. J. Pharmac. 108, 163-9, 1985. Results of the test are presented in Table 2, where the ability of the studied agents to compete with 3 H-clonidine and 3 H-prazosin binding is expressed as the IC 50 -value (molar concentration of the competing ligand needed to displace 50 percent of the radioactive ligand).
  • the sedative-analgesic properties of the compounds were studied in the spontaneous motility and writhing-test in the mouse. Spontaneous motility of mice and rats was measured using the Animex-activity meter. The test compounds were administered i.p. 30 minutes before the measuring periods of two minutes. In the writhing test the compounds studied and saline were administered s.c. to rats, and 45 min. later 1 ml of 1% acetic acid was administered i.p. The number of writhes was recorded in the following 25 min. period (Koster et al., Fred. Proc. 18: 412, 1959). Results are shown in Tables 3 and 4.
  • the d-enantiomer has an enhanced sedative/analgesic property compared to the racemic mixture (medetomidine) and other reference compounds.
  • the sedative/analgesic effects of medetomidine are confined to the d-enantiomer.
  • the antihypertensive properties of the compounds of the invention have been studied as follows: Sprague-Dawley rats of normal weight were first anesthetized with urethane. After this, the femoral artery was connected by a polyethylene tube to a blood pressure transducer. The test substance was then injected into the femoral vein and the blood pressure and the pulse frequency were registered with a recorder. Results are shown in Table 7.
  • the pharmaceutical carriers which are typically employed with the compounds of the present invention may be solid or liquid and are generally selected with the planned manner of administration in mind.
  • solid carriers include lactose, sucrose, gelatin and agar
  • liquid carriers include water, syrup, peanut oil and olive oil.
  • suitable carriers are well known to those skilled in the art of pharmaceutical formulations.
  • the combination of the derivative and the carrier may be fashioned into numerous acceptable forms, such as tablets, capsules, suppositories, solutions, emulsions, and powders.

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Abstract

The separated d and l enantiomers of medetomidine and their salts are selective and potent α2 -receptor agonists.

Description

This invention relates to optical isomers of imidazole derivatives and to their preparation.
Medetomidine which has the formula: ##STR1## is known as a selective and potent α2 -receptor agonist. It has been described, e.g. in European Patent Publication No. 72615, as an antihypertensive agent and in the European Patent Publication No. 187471 as a veterinary sedative-analgesic agent.
The present invention provides, as new compounds, the optically active d- and l-enantiomers of medetomidine, and their non-toxic pharmaceutically acceptable acid addition salts. These compounds may be represented by the formulae: ##STR2##
According to a feature of the invention, racemic medetomidine is separated into the enantiomers II and III by conversion of the racemate into a mixture of diastereoisomers and separating the latter by fractional crystallization. Since medetomidine is a base, it may be converted into a diastereoisomer salt mixture by reaction with an optically active acid such as (+)-tartaric acid. Other useful optically active acids are, e.g., (-)-malic acid, (-)-mandelic acid and (+)-camphor-10-sulfonic acid. (+)-Tartaric acid is especially useful for the resolution. The separation of the diastereisomers is performed by repeated crystallizing from an alcohol such as methanol or ethanol or a mixture of them.
Once the diastereoisomers have been separated the acid addition salts can be converted back to the free bases by making their aqueous solutions alkaline with sodium hydroxide and by extracting the liberated base in an appropriate organic solvent such as methylene chloride.
The d- and l-enantiomers of medetomidine react with organic and inorganic acids to form the corresponding acid addition salts, which have the same therapeutic activities as the bases. They can thus form many pharmaceutically usable acid addition salts, as, for instance, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
The d- and l-enantiomers of medetomidine are selective and potent α2 -receptor agonists.
Adrenergic receptors are physiologically important binding sites which are specific to noradrenaline and adrenaline and located on the surface of the cell membrane. The adrenoceptors of the sympathetic nervous system have been classified into two different subtypes, alpha-(α) and beta-(β) receptors, which can be further divided into two subgroups, viz α1 and α2 and β1 and β2. Of these receptor types, β1, β2 and α1 are mainly located post-synaptically on the surface of, e.g., smooth muscle and thus mediate, e.g., smooth muscle contraction or relaxation; whereas α2 receptors are mainly located presynaptically on the terminals of noradrenergic nerves. If α2 -receptors are stimulated by noradrenaline under physiological conditions noradrenaline release is blocked, i.e. there is a negative feed-back phenomenon. This negative feed-back phenomenon may also be induced by certain synthetic α2 -agonists like medetomidine and some of its near derivatives.
In animal experiments, the d- and l- enantiomers of the present invention and especially the d-enantiomer, have proved to possess highly enhanced α2 -selectivity and potency compared to the racemic mixture (i.e. medetomidine). The d-enantiomer can be expected to be of value, e.g., as a sedative-analgesic, anxiolytic or antihypertensive agent. Furthermore, it can be used as a pharmacological tool in the study of the physiology and pharmacology of α2 -adrenoceptors.
The pharmacological activity of the compounds of the invention was determined as follows:
1. ALPHA-2 AGONISM IN VITRO
α2 -agonism was determined by means of isolated, electrically stimulated mouse was deferens preparation (Marshall et al., Br. J. Pharmac. 62, 147-151, 1978). In this model, an α2 -agonist is able to block electrically induced muscular contractions by activating the presynaptic α2 -adrenoceptors and thus diminishing the secretion on the motor transmitter. Known α2 -agonists like detomidine, medetomidine and clonidine were used as reference substances. Results are shown in Table 1, where the α2 -agonist effect is presented as the pD2 -value (negative logarith of the molar concentration of the compound producing 50 percent of maximal inhibition.)
              TABLE 1                                                     
______________________________________                                    
             α.sub.2 -agonism in vitro (mouse                       
Compound     vas deferens). pD.sub.2                                      
______________________________________                                    
d-enantiomer 9.3                                                          
1-enantiomer 6.0 (partial agonist)                                        
medetomidine 9.0                                                          
detomidine   8.5                                                          
clonidine    8.5                                                          
______________________________________
These results show that the α2 -agonist activity of medetomidine is limited to the d-enantiomer. The d-enantiomer shows an enhanced α2 -agonist activity compared to the outer agents studied.
2. α2 /α1 -SELECTIVITY IN VITRO
The selectivity of the d-enantiomer as an α2 -agonist was studied in receptor binding experiments using rat brain membranes. The ability of the d-isomer and the reference compounds to compete with 3 H-clonidine (for α2 -receptors) and 3 H-prazosin (for α1 -receptors) was studied essentially as described by Virtanen and Nyman in Eur. J. Pharmac. 108, 163-9, 1985. Results of the test are presented in Table 2, where the ability of the studied agents to compete with 3 H-clonidine and 3 H-prazosin binding is expressed as the IC50 -value (molar concentration of the competing ligand needed to displace 50 percent of the radioactive ligand).
              TABLE 2                                                     
______________________________________                                    
          .sup.3 H-clonidine                                              
                      .sup.3 H-prazosin                                   
          displacement                                                    
                      displacement                                        
                                  α.sub.2 /α.sub.1 -          
Compound  IC.sub.50, nM                                                   
                      IC.sub.50, nM                                       
                                  selectivity                             
______________________________________                                    
d-enantiomer                                                              
          1.2         55019       45849                                   
1-enantiomer                                                              
          46          189975      4129                                    
medetomidine                                                              
          3.3         16700       5060                                    
detomidine                                                                
          3.7         242         65                                      
clonidine 6.4         6200        969                                     
______________________________________
The results show that the d-enantiomer is an extremely selective α2 -agonist compared to medetomidine and the other reference compounds. 3. SEDATIVE ANALGESIC EFFECTS
The sedative-analgesic properties of the compounds were studied in the spontaneous motility and writhing-test in the mouse. Spontaneous motility of mice and rats was measured using the Animex-activity meter. The test compounds were administered i.p. 30 minutes before the measuring periods of two minutes. In the writhing test the compounds studied and saline were administered s.c. to rats, and 45 min. later 1 ml of 1% acetic acid was administered i.p. The number of writhes was recorded in the following 25 min. period (Koster et al., Fred. Proc. 18: 412, 1959). Results are shown in Tables 3 and 4.
              TABLE 3                                                     
______________________________________                                    
ED.sub.50 -values of the studied compounds                                
in reducing spontaneous motility in mice                                  
Compound      ED.sub.50 (mg/kg s.c.)                                      
______________________________________                                    
d-enantiomer  0.02                                                        
1-enantiomer  >10                                                         
medetomidine  0.05                                                        
detomidine     0.3                                                        
clonidine      0.3                                                        
______________________________________                                    

              TABLE 4                                                     
______________________________________                                    
ED.sub.50 -values of the studied compounds                                
in acetic acid-induced writhing test in mice                              
Compound      ED.sub.50 (mg/kg s.c.)                                      
______________________________________                                    
d-enantiomer  0.01                                                        
1-enantiomer  >10                                                         
medetomidine  0.02                                                        
detomidine    0.02                                                        
clonidine     0.03                                                        
______________________________________
These results shown that the d-enantiomer has an enhanced sedative/analgesic property compared to the racemic mixture (medetomidine) and other reference compounds. The sedative/analgesic effects of medetomidine are confined to the d-enantiomer.
4. ANXIOLYTIC EFFECTS
The anxiolytic effects of the compounds were studied using a method described by Handley and Mithoni: Naunyn-Schmiedeb, Arch. Pharmacol. 327, 1-5, 1984. In this test the manner of exploration of open and enclosed arms in an elevated t-maze by a rat is examined. It has been shown that anxiolytic drugs increase the relative exploration of open arms. A rat is placed in the center of the t-maze and the number of open and enclosed entries is recorded during 5 minutes. Results obtained are shown in Table 5.
              TABLE 5                                                     
______________________________________                                    
           Mean number of entries (n = 6)                                 
Drug/dose, mg/kg                                                          
             open    closed   total open/total                            
______________________________________                                    
NaCl         3.4      8.6     12.0  0.28                                  
d-enantiomer                                                              
0.0003       4.8     10.6     14.0  0.20                                  
0.001        3.2     10.6     13.8  0.23                                  
0.003        4.0      9.5     13.5  0.29                                  
0.01         5.8      8.8     14.6  0.39                                  
0.03         2.5      3.0      5.5  0.45                                  
diazepam                                                                  
1            5.2     10.5     15.7  0.33                                  
______________________________________
The results show that the d-enantiomer has an anxiolytic profile in the elevated t-maze test.
It is well known that anxiety states connected to withdrawal symptoms are due to noradrenergic hyperactivity. Therefore such symptoms can be successfully treated with drugs reducing the level of noradrenaline, e.g. clonidine. Experiments in the rat indicate that the d-enantiomer is able to reduce noradrenaline release and thus sympathetic tone both in the central and peripheral nervous systems. This has clearly been demonstrated by measuring CSF-concentrations of MHPG-SO4 (the principal metabolite of central noradrenaline) in the rat after d-enantiomer administration. The results are shown in Table 6.
              TABLE 6                                                     
______________________________________                                    
d-enantiomer dose                                                         
             CSF MHPG-SO.sub.4 (% of control)                             
μg/kg     (4 h after d-enantiomer adm.)                                
______________________________________                                    
 0            100                                                         
 3           -10                                                          
10           -20                                                          
30           -30                                                          
100          -65                                                          
______________________________________
5. ANTIHYPERTENSIVE EFFECTS
The antihypertensive properties of the compounds of the invention have been studied as follows: Sprague-Dawley rats of normal weight were first anesthetized with urethane. After this, the femoral artery was connected by a polyethylene tube to a blood pressure transducer. The test substance was then injected into the femoral vein and the blood pressure and the pulse frequency were registered with a recorder. Results are shown in Table 7.
              TABLE 7                                                     
______________________________________                                    
Antihypertensive effects of                                               
the d-enantiomer in anesthetized rats                                     
Dose, mg/kg                                                               
          Decrease in BP, %                                               
                       Decrease in heart rate, %                          
______________________________________                                    
0.001      -8          -21                                                
0.003     -23          -40                                                
 0.01     -43          -47                                                
 0.03     -45          -48                                                
 0.1      -45          -50                                                
______________________________________
The results show that the d-enantiomer possesses clear anti-hypertensive and bradycardia effects.
The d- and l-enantiomers, and their non-toxic, pharmaceutically acceptable acid addition salts or mixtures thereof may be administered parenterally, intravenously or orally. Typically, an effective amount of the compound is combined with a suitable pharmaceutical carrier. As used herein, the term "effective amount" encompasses those amounts which yield the desired activity without causing adverse side-effects. The precise amount employed in a particular situation is dependent upon numerous factors such as method of administration, type of mammal, condition for which the derivative is administered, etc. and of course the structure of the derivative.
The pharmaceutical carriers which are typically employed with the compounds of the present invention may be solid or liquid and are generally selected with the planned manner of administration in mind. Thus, for example, solid carriers include lactose, sucrose, gelatin and agar, while liquid carriers include water, syrup, peanut oil and olive oil. Other suitable carriers are well known to those skilled in the art of pharmaceutical formulations. The combination of the derivative and the carrier may be fashioned into numerous acceptable forms, such as tablets, capsules, suppositories, solutions, emulsions, and powders.
The following Example illustrates the separation of the new enantiomers.
EXAMPLE
14 g of medetomidine (base) were dissolved in 50 ml of methanol. 10.5 g of (+)-tartaric acid were dissolved in 50 ml of methanol. The solutions were mixed and the solvent was evaporated to a volume of 50 ml. The mixture was put into an ice bath and 9 g of white precipitate was obtained. The precipitate was suspended in 25 ml of ethanol, the mixture was kept in ultrasonic sound for 14 min and filtered. The precipitate was dissolved in a mixture of 20 ml abs. ethanol and 60 ml methanol by heating on a steam bath. After cooling, 5 g of precipitate (degree of rotation +55°) was obtained. After recrystallization from 60 ml of methanol, 4.1 g of product was obtained, degree of rotation +60°. Recrystallization was repeated until the degree of rotation did not increase any longer. The d-enantiomer tartrate was dissolved in water, the solution was made alkaline and the d-enantiomer was dissolved in an organic solvent e.g. dichlormethane or diethyl ether. The degree of rotation of the d-enantiomer base was +75°.
The l-enantiomers may be isolated from the mother liquors.

Claims (4)

We claim:
1. The d enantiomer of medetomidine or a non-toxic pharmaceutically acceptable acid addition salt thereof.
2. A pharmaceutical composition suitable for use in a method of sedation/analgesia or treatment of anxiety or hypertension comprising the d-enantiomer of medetomidine or a non-toxic pharmaceutically acceptable acid addition salt thereof in an amount sufficient to produce the desired effect in association with a pharmaceutical carrier.
3. A method of sedation/analgesia or treatment of anxiety or hypertension by administration to a subject of an effective amount of an enantiomer according to claim 1.
4. A method of sedation/analgesia or treatment of anxiety or hypertension by administration to a subject of an effective amount of a composition according to claim 2.
US07/219,637 1987-07-16 1988-07-15 Optical isomer of an imidazole derivative medetomidine as an alpha-2-receptor agonist Expired - Lifetime US4910214A (en)

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US9795559B2 (en) 2011-12-11 2017-10-24 Recro Pharma, Inc. Intranasal dexmedetomidine compositions and methods of use thereof
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US5124157A (en) * 1989-08-18 1992-06-23 Cygnus Therapeutic Systems Method and device for administering dexmedetomidine transdermally
AU639015B2 (en) * 1989-08-18 1993-07-15 Cygnus, Inc. Method and device for administering dexmedetomidine transdermally
WO1991002505A1 (en) * 1989-08-18 1991-03-07 Cygnus Research Corporation Method and device for administering dexmedetomidine transdermally
US5120713A (en) * 1990-09-10 1992-06-09 Applied Research Systems Ars Holding N.V. Treatment of obesity with an alpha-2-adrenergic agonist and a growth hormone releasing peptide
US5658938A (en) * 1994-12-14 1997-08-19 U C B S.A. Substituted 1H-imidazoles
US6716867B1 (en) 1998-04-01 2004-04-06 Orion Corporation Use of dexmedetomidine for ICU sedation
BG64540B1 (en) * 1998-04-01 2005-07-29 Orion Corporation Use of dexmedetomidine for sedative effect in patients in an intensive care unit
US8470862B2 (en) 1999-10-29 2013-06-25 Recro Pharma, Inc. Treatment or prevention of hypotension and shock
US9446025B2 (en) 1999-10-29 2016-09-20 Recro Pharma, Inc. Treatment or prevention of hypotension and shock
US9078883B2 (en) 1999-10-29 2015-07-14 Recro Pharma, Inc. Treatment or prevention of hypotension and shock
US6388090B2 (en) * 2000-01-14 2002-05-14 Orion Corporation Imidazole derivatives
EP2218442A1 (en) 2005-11-09 2010-08-18 CombinatoRx, Inc. Methods, compositions, and kits for the treatment of ophthalmic disorders
US10086087B2 (en) 2006-03-16 2018-10-02 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
US20100010006A1 (en) * 2008-07-08 2010-01-14 Lance William R Pharmaceutical Combination for and Method of Anesthetizing and Immobilizing Non-Domesticated Mammals
US7795263B2 (en) 2008-07-08 2010-09-14 Wildlife Laboratories, Inc. Pharmaceutical combination for and method of anesthetizing and immobilizing non-domesticated mammals
US20100196286A1 (en) * 2008-12-01 2010-08-05 Armer Thomas A Inhalation delivery methods and devices
US9161912B2 (en) 2008-12-23 2015-10-20 Map Pharmaceuticals, Inc. Inhalation devices and related methods for administration of sedative hypnotic compounds
US20100192945A1 (en) * 2008-12-23 2010-08-05 Robert Owen Cook Inhalation devices and related methods for administration of sedative hypnotic compounds
US8555875B2 (en) 2008-12-23 2013-10-15 Map Pharmaceuticals, Inc. Inhalation devices and related methods for administration of sedative hypnotic compounds
US20110021588A1 (en) * 2009-05-15 2011-01-27 Recro Pharma, Inc. Sublingual dexmeditomidine compositions and methods of use thereof
US9314449B2 (en) 2011-10-14 2016-04-19 Hospira, Inc. Methods of treating pediatric patients using dexmedetomidine
WO2013069025A1 (en) 2011-11-11 2013-05-16 Neon Laboratories Ltd. "process for the preparation of dexmedetomidine"
US9795559B2 (en) 2011-12-11 2017-10-24 Recro Pharma, Inc. Intranasal dexmedetomidine compositions and methods of use thereof
US10682311B2 (en) 2011-12-11 2020-06-16 Baudax Bio, Inc. Intranasal dexmedetomidine compositions and methods of use thereof
US8648106B2 (en) 2012-01-04 2014-02-11 Hospira, Inc. Dexmedetomidine premix formulation
US8455527B1 (en) 2012-01-04 2013-06-04 Hospira, Inc. Methods of treatment using a dexmedetomidine premix formulation
US9320712B2 (en) 2012-01-04 2016-04-26 Hospira, Inc. Dexmedetomidine premix formulation
US8436033B1 (en) 2012-01-04 2013-05-07 Hospira, Inc. Methods of treatment using a dexmedetomidine premix formulation
US9616049B2 (en) 2012-01-04 2017-04-11 Hospira, Inc. Dexmedetomidine premix formulation
EP3345599A1 (en) 2012-01-04 2018-07-11 Hospira, Inc. Dexmedetomidine premix formulation
US10016396B2 (en) 2012-01-04 2018-07-10 Hospira, Inc. Dexmedetomidine premix formulation
US8877941B2 (en) * 2012-02-29 2014-11-04 Edmond Pharma S.R.L. Process for the resolution of medetomidine and recovery of the unwanted enantiomer
US20130225832A1 (en) * 2012-02-29 2013-08-29 Edmond Pharma S.R.L. Process for the resolution of medetomidine and recovery of the unwanted enantiomer
US11103494B2 (en) 2012-08-15 2021-08-31 Tris Pharma, Inc Methylphenidate extended release chewable tablet
US10507203B2 (en) 2012-08-15 2019-12-17 Tris Pharma, Inc Methylphenidate extended release chewable tablet
US9844545B2 (en) 2012-08-15 2017-12-19 Tris Pharma, Inc. Methylphenidate extended release chewable tablet
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US10780079B2 (en) 2012-10-15 2020-09-22 Orion Corporation Veterinary method of alleviating noise aversion
US9649296B1 (en) 2016-04-20 2017-05-16 Slypharma, Llc. Heat sterilizeable, premixed, ready to use dexmedetomidine solution packaged in a flexible plastic container
US11160791B2 (en) 2018-11-01 2021-11-02 Medefil, Inc. Dexmedetomidine injection premix formulation in ready to use (RTU) bags
CN114671811A (en) * 2022-04-14 2022-06-28 南京正科医药股份有限公司 Racemization recovery method of dexmedetomidine resolution byproduct

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